Use of an agent for treating the symptoms of Parkinson&#39;s disease

ABSTRACT

With an agent for preparing a medication for treating the symptoms of Parkinson&#39;s disease, one obtains more effective treatment of the symptoms of said disease compared to classical treatment by a combination of effective substances comprising a substance increasing dopamine concentration in the synaptic cleft of the neurons of the brain along with a local anesthetic of the anilide group.

CROSS REFERENCE TO RELATED APPLICATIONS

Applicant claims priority under 35 U.S.C. § 119 of German ApplicationNo. 198 55 704.3 filed Dec. 3, 1998. Applicant claim priority under 35U.S.C. § 120 of PCT/DE98/03612 filed Dec. 9, 1998. The internationalapplication under PCT article 21(2) was not published in English.

This invention relates to a use of an agent having a substanceincreasing the dopamine concentration in the synaptic cleft of theneurons of the brain.

The invention relates to an agent for preparing a medication fortreating the symptoms of Parkinson's disease.

In the classical treatment of Parkinson's disease the main effectivesubstance used is levodopa, also known as L-Dopa. Levodopa is aprecursor of dopamine and, unlike the latter, capable of crossing theblood-brain barrier after an application. After crossing the blood-brainbarrier, levodopa is converted to dopamine in the brain. The substancedopamine acts in the brain as a neurotransmitter in the synaptic cleftof the neurons of the brain in such a way as to promote signaltransmission from one cell to another. The concentration of dopamine isdeficient in the brains of persons suffering from Parkinson's disease sothat signal transmission is impaired from one neuron to another in thebrain. The administration of levodopa to parkinsonian patients increasesdopamine concentration in the synaptic cleft of the neurons of thebrain, thereby improving signal transmission between the neurons of thebrain and improving control of motor and intellectual processes.

In addition to levodopa, the classical treatment of Parkinson's diseaseinvolves the administration of substances which promote the effect ofdopamine called dopamine-promoting agonists. Dopamine-promoting agonistsgenerally act in such a way that dopamine concentration in the synapticcleft of the neurons of the brain remains increased through inhibitionof the breakdown of dopamine there. Normal breakdown of dopamine iscaused by it being broken down to noradrenaline by an enzyme,monooxygenase.

Formation of monooxygenase can be inhibited by certaindopamine-promoting agonists so that dopamine can only be broken down tonoradrenaline to a diminished degree and a given concentration ofdopamine in the synaptic cleft is consequently maintained longer.Alternatively the mode of action of dopamine-promoting agonists can bebased on releasing dopamine stored in storage sites of the brain andinhibiting reassimilation in the storage site. Dopamine-promotingagonists include bromocriptine, selegiline, amantadine, pergolidemesylate or tolcapone. A further known dopamine-promoting agonist isNORMA BRAIN® (piracetam) whose effect is based on generally improvingcerebral blood flow.

The problem of the invention is to find a use for an agent which reducesthe symptoms of Parkinson's disease when taken alone, but in particularin combination with known agents.

For a use of the abovementioned kind this problem is solved by adding alocal anesthetic of the anilide group or its derivatives as an effectivesubstance for preparing a medication for treating the symptoms ofParkinson's disease.

Preferred embodiments of the invention are the subject matter of thesubclaims.

According to a preferred embodiment of the inventive use, the localanesthetic of the anilide group chosen is the substance mepivacaine,preferably in a daily dose of 30 mg to 60 mg. Alternatively tomepivacaine one can use the substances lidocaine, bupivacaine,butanilicaine, tolycaine or etidocaine.

The inventive use has the effect, upon application to parkinsonianpatients, that the specific symptoms of Parkinson's disease clearlysubside, the resulting improved condition of the patient continuing forseveral hours and even days. In particular, a clear improvement ofdisease-specific symptoms was obtained with the inventive use insofar as

motoricity and fine motoricity were improved

mobility was increased

concentration power was increased

reaction time was decreased

pronunciation was improved

power of comprehension was improved

state of mind was brightened and emotional condition improved.

With the inventive use, the combination of a substance increasingdopamine concentration in the synaptic cleft of the neurons of the brainwith a local anesthetic of the anilide group possibly results in anincrease in the permeability of the blood-brain barrier for thesubstance levodopa, so that dopamine can accumulate in higherconcentration in the brain of a person suffering from Parkinson'sdisease than with standard treatment, thereby obtaining a higherconcentration of dopamine in such a person's brain. In addition, itpossibly increases the retention time of dopamine in the brain.

The substance “local anesthetic of the anilide group” essential to theinventive use belongs in general to the local anesthetics of differentstructure, the local anesthetics of the anilide group and theirderivatives being preferred for treatment as a subgroup of said localanesthetics. Examples of said subgroup are not only mepivacaine but alsolidocaine, bupivacaine, butanilicaine, etidocaine and tolycaine.Mepivacaine has the smallest molecule of said group, and said substancehas also proved most effective in treating patients with Parkinson'sdisease. One supposition is that the small molecular size of mepivacaineprovides an increased probability of crossing the blood-brain barrier.Mepivacaine is in addition lipophilic, i.e. lipid-loving, and tends toattach to fat molecules. It is remarkable in this connection thatneurons are usually embedded in fat and an accumulation or concentrationof mepivacaine in fat will presumably also have effects on the nervouspathways running through fatty tissue. Levodopa also has stronglipophilia, like mepivacaine, so that this connection might also providea mechanism of action.

In the inventive use for treating the symptoms of Parkinson's disease,levodopa is preferably applied in a daily dose of 200 mg to 600 mg.

According to an alternative embodiment of the inventive use, thesubstance increasing dopamine concentration in the synaptic cleft of theneurons of the brain additionally contains bromocriptine, which ispreferably applied in a daily dose of 1.25 mg to 10 mg.

According to another embodiment of the inventive use, the substanceincreasing dopamine concentration in the synaptic cleft of the neuronsof the brain additionally contains selegiline, which is preferablyapplied in a daily dose of 4 mg to 20 mg.

According to another alternative embodiment of the inventive use, thesubstance increasing dopamine concentration in the synaptic cleft of theneurons of the brain additionally contains amantadine, which ispreferably applied in a daily dose of 100 mg to 400 mg.

According to another alternative embodiment of the inventive use, thesubstance increasing dopamine concentration in the synaptic cleft of theneurons of the brain additionally contains pergolide mesylate, which ispreferably applied in a daily dose of 2 mg to 8 mg. The inventive agent,according to another embodiment, can also contain tolcapone as asubstance increasing dopamine concentration in the synaptic cleft of theneurons of the brain, which is applied in a daily dose of 100 mg to 400mg.

According to another inventive embodiment of the inventive use, thesubstance increasing dopamine concentration in the synaptic cleft of theneurons of the brain could additionally contain piracetam, which isapplied in a daily dose of 1,000 mg to 4,000 mg.

The abovementioned substances increasing dopamine concentration in thesynaptic cleft of the neurons of the brain can according to theinvention be contained in the inventive use of an agent both each per seand in different combinations with each other. However, the effect ofthe agent is based not so much on a special combination of substancesincreasing dopamine concentration in the synaptic cleft of the neuronsof the brain as used in classical parkinsonian treatment, but rather ona combination of said substances classically used for parkinsoniantreatment with a local anesthetic, in particular a local anesthetic ofthe anilide group and more particularly, but not exclusively, with thesubstance mepivacaine.

The stated doses of local anesthetics are based on applications byinjection. For oral application the dose is to be adapted accordingly.

What is claimed is:
 1. A method for treating the symptoms of Parkinson'sdisease comprising: administering to a person in need of treating, atherapeutically effective amount of a substance which increases Dopamineconcentration in the synaptic cleft of the neurons of the brain, incombination with an effective amount of a local anesthetic of theanilide group or derivatives thereof, wherein the local anesthetic ofthe anilide group is selected from the group consisting of mepivacaine,bupivacaine, butanilicaine, tolycaine, etidocaine, and mixtures thereof.2. The method according to claim 1, wherein the local anesthetic of theanilide group is mepivacaine.
 3. The method according to claim 2,wherein mepivacaine is applied in a daily dose of 30 mg to 60 mg.
 4. Themethod according to claim 1, wherein the local anesthetic of the anilidegroup is bupivacaine.
 5. The method according to claim 4, whereinbupivacaine is applied in a daily dose of up to 150 mg.
 6. The methodaccording to claim 1, wherein the local anesthetic of the anilide groupis butanilicaine.
 7. The method according to claim 1, wherein the localanesthetic of the anilide group is tolycaine.
 8. The method according toclaim 1, wherein the local anesthetic of the anilide group isetidocaine.
 9. The method according to claim 1, wherein the substancewhich increases dopamine concentration in the synaptic cleft of theneurons of the brains is LevoDopa and is applied in a daily dose of 200mg to 600 mg.
 10. The method according to claim 1, wherein the substanceincreasing dopamine concentration in the synaptic cleft of the neuronsof the brain additionally contains bromocriptine.
 11. The methodaccording to claim 10, wherein bromocriptine is applied in a daily doseof 1.0 mg to 10 mg.
 12. The method according to claim 1, wherein thesubstance increasing dopamine concentration in the synaptic cleft of theneurons of the brain additionally contains selegiline.
 13. The methodaccording to claim 12, wherein selegiline is applied in a daily dose of4 mg to 20 mg.
 14. The method according to claim 1, wherein thesubstance increasing dopamine concentration in the synaptic cleft of theneurons of the brain additionally contains amantadine.
 15. The methodaccording to claim 14, wherein amantadine is applied in a daily dose of100 mg to 400 mg.
 16. The method according to claim 1, wherein thesubstance increasing dopamine concentration in the synaptic cleft of theneurons of the brain additionally contains pergolide mesylate.
 17. Themethod according to claim 16, wherein pergolide mesylate is applied in adaily dose of 2 mg to 8 mg.
 18. The method according to claim 1, whereinthe substance increasing dopamine concentration in the synaptic cleft ofthe neurons of the brain additionally contains tolcapone.
 19. The methodaccording to claim 18, wherein tolcapone is applied in a daily dose of100 mg to 400 mg.
 20. The method according to claim 1, wherein thesubstance increasing dopamine concentration in the synaptic cleft of theneurons of the brain additionally contains piracetam.
 21. The methodaccording to claim 20, wherein piracetam is applied in a daily dose of1000 mg to 4000 mg.